In domestic animals and humans, optimal fetal growth is predicated on sufficient nutrient delivery across the placenta. Our long-range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating placental growth and function to support optimal fetal growth. Importantly, impaired fetal growth is associated with increased incidence of neonatal morbidity and mortality in both livestock species and humans. In addition, emerging evidence related to developmental origins of adult-onset disease highlight the additional long- term consequences of a poor uterine environment on lifelong health. The goal of this proposal is to capitalize on natural population variance using the sheep, (serving as both an agriculturally important food animal as well as an accepted biomedical model for studies related to humans) to elucidate the mechanisms by which the placenta can adapt to maternal malnutrition to support varying degrees of fetal growth. To achieve this goal we will conduct a series of nutritional studies using singleton pregnant ewes of similar body size and condition, carrying embryos generated from similar males and superovulated donor females. We have previously employed this strategy and observed increased variance in levels of fetal growth in nutrient restricted ewes. We will capitalize on thi natural population variance by comparing the upper and lower quartiles of individuals based upon fetal growth to elucidate mechanisms controlling placental growth and function. Specific aims are to: 1) elucidate the relative contributions of fetal genotype and the host uterine environment on fetal development; 2) investigate mechanisms governing placental vascular growth and function in nutrient-restricted ewes; and 3) identify the contribution of select nutriens in regulating placental growth and function in nutrient-restricted ewes. This research is innovative because it will develop a unique animal model for the study of placental growth, function, and adaptation. In addition, we will employ novel surgical strategies allowing for retrospective analysis of early placental gene expression based on rates of fetal growth in late gestation. Completion of the proposed research is expected to fill a critical gap in our existing knowledge by providing novel insights into placental growth and function as they relate to the spectrum of observed rates of fetal growth. Translational outcomes of the proposed research include biomarkers for placental function as well as the identification of novel nutritional and genetic targets for the development of therapeutic strategies to enhance fetal growth in undernourished mothers.